Regulation and Functions of Autophagy During Animal Development.

Autophagy is used to degrade cytoplasmic materials, and is critical to maintain cell and organismal health in diverse animals. Here we discuss the regulation, utilization and impact of autophagy on development, including roles in oogenesis, spermatogenesis and embryogenesis in animals. We also describe how autophagy influences postembryonic development in the context of neuronal and cardiac development, wound healing, and tissue regeneration. We describe recent studies of selective autophagy during development, including mitochondria-selective autophagy and endoplasmic reticulum (ER)-selective autophagy. Studies of developing model systems have also been used to discover novel regulators of autophagy, and we explain how studies of autophagy in these physiologically relevant systems are advancing our understanding of this important catabolic process.

PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.

Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.

Synaptic Development in Diverse Olfactory Neuron Classes Uses Distinct Temporal and Activity-Related Programs.

Developing neurons must meet core molecular, cellular, and temporal requirements to ensure the correct formation of synapses, resulting in functional circuits. However, because of the vast diversity in neuronal class and function, it is unclear whether or not all neurons use the same organizational mechanisms to form synaptic connections and achieve functional and morphologic maturation. Moreover, it remains unknown whether neurons united in a common goal and comprising the same sensory circuit develop on similar timescales and use identical molecular approaches to ensure the formation of the correct number of synapses. To begin to answer these questions, we took advantage of the Drosophila antennal lobe (AL), a model olfactory circuit with remarkable genetic access and synapse-level resolution. Using tissue-specific genetic labeling of active zones, we performed a quantitative analysis of synapse formation in multiple classes of neurons of both sexes throughout development and adulthood. We found that olfactory receptor neurons (ORNs), projection neurons (PNs), and local interneurons (LNs) each have unique time courses of synaptic development, addition, and refinement, demonstrating that each class follows a distinct developmental program. This raised the possibility that these classes may also have distinct molecular requirements for synapse formation. We genetically altered neuronal activity in each neuronal subtype and observed differing effects on synapse number based on the neuronal class examined. Silencing neuronal activity in ORNs, PNs, and LNs impaired synaptic development but only in ORNs did enhancing neuronal activity influence synapse formation. ORNs and LNs demonstrated similar impairment of synaptic development with enhanced activity of a master kinase, GSK-3ß, suggesting that neuronal activity and GSK-3ß kinase activity function in a common pathway. ORNs also, however, demonstrated impaired synaptic development with GSK-3ß loss-of-function, suggesting additional activity-independent roles in development. Ultimately, our results suggest that the requirements for synaptic development are not uniform across all neuronal classes with considerable diversity existing in both their developmental time frames and molecular requirements. These findings provide novel insights into the mechanisms of synaptic development and lay the foundation for future work determining their underlying etiologies.SIGNIFICANCE STATEMENT Distinct olfactory neuron classes in Drosophila develop a mature synaptic complement over unique timelines and using distinct activity-dependent and molecular programs, despite having the same generalized goal of olfactory sensation.

Residues forming the gating regions of asymmetric multidrug transporter Pdr5 also play roles in conformational switching and protein folding.

ATP-binding cassette (ABC) multidrug transporters are large, polytopic membrane proteins that exhibit astonishing promiscuity for their transport substrates. These transporters unidirectionally efflux thousands of structurally and functionally distinct compounds. To preclude the reentry of xenobiotic molecules via the drug-binding pocket, these proteins contain a highly conserved molecular gate, essentially allowing the transporters to function as molecular diodes. However, the structure-function relationship of these conserved gates and gating regions are not well characterized. In this study, we combine recent single-molecule, cryo-EM data with genetic and biochemical analyses of residues in the gating region of the yeast multidrug transporter Pdr5, the founding member of a large group of clinically relevant asymmetric ABC efflux pumps. Unlike the symmetric ABCG2 efflux gate, the Pdr5 counterpart is highly asymmetric, with only four (instead of six) residues comprising the gate proper. However, other residues in the near vicinity are essential for the gating activity. Furthermore, we demonstrate that residues in the gate and in the gating regions have multiple functions. For example, we show that Ile-685 and Val-1372 are required not only for successful efflux but also for allosteric inhibition of Pdr5 ATPase activity. Our investigations reveal that the gating region residues of Pdr5, and possibly other ABCG transporters, play a role not only in molecular gating but also in allosteric regulation, conformational switching, and protein folding.

γ-secretase promotes Drosophila postsynaptic development through the cleavage of a Wnt receptor.

Developing synapses mature through the recruitment of specific proteins that stabilize presynaptic and postsynaptic structure and function. Wnt ligands signaling via Frizzled (Fz) receptors play many crucial roles in neuronal and synaptic development, but whether and how Wnt and Fz influence synaptic maturation is incompletely understood. Here, we show that Fz2 receptor cleavage via the γ-secretase complex is required for postsynaptic development and maturation. In the absence of γ-secretase, Drosophila neuromuscular synapses fail to recruit postsynaptic scaffolding and cytoskeletal proteins, leading to behavioral deficits. Introducing presenilin mutations linked to familial early-onset Alzheimer's disease into flies leads to synaptic maturation phenotypes that are identical to those seen in null alleles. This conserved role for γ-secretase in synaptic maturation and postsynaptic development highlights the importance of Fz2 cleavage and suggests that receptor processing by proteins linked to neurodegeneration may be a shared mechanism with aspects of synaptic development.

Machine Learning Automated Detection of Large Vessel Occlusion From Mobile Stroke Unit Computed Tomography Angiography.

BACKGROUND: Prehospital automated large vessel occlusion (LVO) detection in Mobile Stroke Units (MSUs) could accelerate identification and treatment of patients with LVO acute ischemic stroke. Here, we evaluate the performance of a machine learning (ML) model on CT angiograms (CTAs) obtained from 2 MSUs to detect LVO. METHODS: Patients evaluated on MSUs in Houston and Los Angeles with out-of-hospital CTAs were identified. Anterior circulation LVO was defined as an occlusion of the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or anterior cerebral artery vessels and determined by an expert human reader. A ML model to detect LVO was trained and tested on independent data sets consisting of in-hospital CTAs and then tested on MSU CTA images. Model performance was determined using area under the receiver-operator curve statistics. RESULTS: Among 68 patients with out-of-hospital MSU CTAs, 40% had an LVO. The most common occlusion location was the middle cerebral artery M1 segment (59%), followed by the internal carotid artery (30%), and middle cerebral artery M2 (11%). Median time from last known well to CTA imaging was 88.0 (interquartile range, 59.5-196.0) minutes. After training on 870 in-hospital CTAs, the ML model performed well in identifying LVO in a separate in-hospital data set of 441 images with area under receiver-operator curve of 0.84 (95% CI, 0.80-0.87). ML algorithm analysis time was under 1 minute. The performance of the ML model on the MSU CTA images was comparable with area under receiver-operator curve 0.80 (95% CI, 0.71-0.89). There was no significant difference in performance between the Houston and Los Angeles MSU CTA cohorts. CONCLUSIONS: In this study of patients evaluated on MSUs in 2 cities, a ML algorithm was able to accurately and rapidly detect LVO using prehospital CTA acquisitions.

Impact of eloquent motor cortex-tissue reperfusion beyond the traditional thrombolysis in cerebral infarction (TICI) scoring after thrombectomy.

BACKGROUND: Targeted eloquence-based tissue reperfusion within the primary motor cortex may have a differential effect on disability as compared with traditional volume-based (thrombolysis in cerebral infarction, TICI) reperfusion after endovascular thrombectomy (EVT) in the setting of acute ischemic stroke (AIS). METHODS: We explored the impact of eloquent reperfusion (ER) within primary motor cortex (PMC) on clinical outcome (modified Rankin Scale, mRS) in AIS patients undergoing EVT. ER-PMC was defined as presence of flow on final digital subtraction angiography (DSA) within four main cortical branches, supplying the PMC (middle cerebral artery (MCA) - precentral, central, postcentral; anterior cerebral artery (ACA) - medial frontal branch arising from callosomarginal or pericallosal arteries) and graded as absent (0), partial (1), and complete (2). Prospectively collected data from two centers were analyzed. Multivariate analysis was conducted to assess the impact of ER-PMC on 90-day disability (mRS) among patients with anterior circulation occlusion who achieved partial reperfusion (TICI 2a and 2b). RESULTS: Among the 125 patients who met the study criteria, ER-PMC distribution was: absent (0) in 19/125 (15.2%); partial (1) in 52/125 (41.6%), and complete (2) in 54/125 (43.2%). TICI 2b was achieved in 102/125 (81.6%) and ER-PMC was substantially higher in those patients (P<0.001). In multivariate analysis, in addition to age and symptomatic intracranial hemorrhage, ER-PMC had a profound independent impact on 90-day disability (OR 6.10, P=0.001 for ER-PMC 1 vs 0 and OR 9.87, P<0.001 for ER-PMC 2 vs 0), while the extent of total partial reperfusion (TICI 2b vs 2a) was not related to 90-day mRS. CONCLUSIONS: Eloquent PMC-tissue reperfusion is a key determinant of functional outcome, with a greater impact than volume-based (TICI) degree of partial reperfusion alone. PMC-targeted revascularization among patients with partial reperfusion may further diminish post-stroke disability after EVT.

Cerebrovascular disease, multiple sclerosis, or both? Case report and review of the challenging distinction between two potentially synergistic syndromes.

White matter changes (WMC) are frequently observed in clinical practice, but their clinical relevance is often obscured by radiology reports that do not clearly convey a likely diagnosis. In this regard, two attitudes contribute to diagnostic confusion: a tendency to dismiss findings as trivial (i.e., using vague characterizations such as "non-specific" or "normal for age"), and a gratuitous dilatation of the differential diagnosis (i.e., routinely adding rare diseases to the list, such as vasculitis). Very often, the finding of WMC presents physicians with a very practical problem, which is to determine whether the underlying etiology is an autoimmune demyelinating disease such as multiple sclerosis (MS), or a vasculopathy such as small vessel cerebrovascular disease (SVCVD). The implications of this distinction are great, because the treatment and prognosis of these two syndromes are very different. Here, we describe the challenging case of a relatively young woman with dementia due to a combination of MS and cerebrovascular disease.

Encephaloduroarteriosynangiosis (EDAS) revascularization for symptomatic intracranial atherosclerotic steno-occlusive (ERSIAS) Phase-II objective performance criterion trial.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is one of the most challenging stroke etiologies, with frequent recurrences despite optimized medical management. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization method that produces extra-cranial collaterals to intracranial vessels. We present the results of a phase-II trial of EDAS in intracranial atherosclerotic disease patients. AIMS: To evaluate the feasibility, safety, and preliminary efficacy of EDAS in intracranial atherosclerotic disease patients. METHODS: ERSIAS was a prospective objective-performance-criterion trial of EDAS plus intensive medical management (IMM) in intracranial atherosclerotic disease (ICAD) patients failing medical treatment. Primary endpoint was any stroke/death within 30-days post-surgery or stroke in the territory of the qualifying artery beyond 30 days. The primary analysis compared event rates through one year with an objective-performance-criterion based on a 10% reduction from the 20% rate in the intensive medical management arm of the stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis trial (SAMMPRIS) in patients with poor collaterals. Event rates through two years were compared with propensity-score-matched (PSM) medically treated patients from SAMMPRIS and the carotid occlusion surgery study (COSS). RESULTS: During a median follow-up of 24.5 months, 5 (9.6%) of 52 patients had a primary endpoint event. The primary endpoint rate at one year met the threshold for nonfutility and advancement to phase III (<10%). In the sensitivity analysis, primary endpoint event rate at two years was lower than in PSM controls, 9.6% versus 21.2% (p < 0.07). Overall, 86% of EDAS-plus-intensive medical management patients were functionally independent at last follow-up and 89% demonstrated neovascularization. There were two (3.8%) surgical complications and no intracranial hemorrhages. CONCLUSION: ERSIAS phase II provides evidence of safety and strong signals of efficacy of EDAS-plus-intensive medical management, supporting advancement to a seamless phase-IIb/III trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov.NCT01819597.

Zinc Finger RNA-Binding Protein Zn72D Regulates ADAR-Mediated RNA Editing in Neurons.

Adenosine-to-inosine RNA editing, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, alters RNA sequences from those encoded by DNA. These editing events are dynamically regulated, but few trans regulators of ADARs are known in vivo. Here, we screen RNA-binding proteins for roles in editing regulation with knockdown experiments in the Drosophila brain. We identify zinc-finger protein at 72D (Zn72D) as a regulator of editing levels at a majority of editing sites in the brain. Zn72D both regulates ADAR protein levels and interacts with ADAR in an RNA-dependent fashion, and similar to ADAR, Zn72D is necessary to maintain proper neuromuscular junction architecture and fly mobility. Furthermore, Zn72D's regulatory role in RNA editing is conserved because the mammalian homolog of Zn72D, Zfr, regulates editing in mouse primary neurons. The broad and conserved regulation of ADAR editing by Zn72D in neurons sustains critically important editing events.

Los Angeles Motor Scale to Identify Large Vessel Occlusion: Prehospital Validation and Comparison With Other Screens.

BACKGROUND AND PURPOSE: Prehospital scales have been developed to identify patients with acute cerebral ischemia (ACI) because of large vessel occlusion (LVO) for direct routing to Comprehensive Stroke Centers (CSCs), but few have been validated in the prehospital setting, and their impact on routing of patients with intracranial hemorrhage has not been delineated. The purpose of this study was to validate the Los Angeles Motor Scale (LAMS) for LVO and CSC-appropriate (LVO ACI and intracranial hemorrhage patients) recognition and compare the LAMS to other scales. METHODS: The performance of the LAMS, administered prehospital by paramedics to consecutive ambulance trial patients, was assessed in identifying (1) LVOs among all patients with ACI and (2) CSC-appropriate patients among all suspected strokes. Additionally, the LAMS administered postarrival was compared concurrently with 6 other scales proposed for paramedic use and the full National Institutes of Health Stroke Scale. RESULTS: Among 94 patients, age was 70 (±13) and 49% female. Final diagnoses were ACI in 76% (because of LVO in 48% and non-LVO in 28%), intracranial hemorrhage in 19%, and neurovascular mimic in 5%. The LAMS administered by paramedics in the field performed moderately well in identifying LVO among patients with ACI (C statistic, 0.79; accuracy, 0.72) and CSC-appropriate among all suspected stroke transports (C statistic, 0.80; accuracy, 0.72). When concurrently performed in the emergency department postarrival, the LAMS showed comparable or better accuracy versus the 7 comparator scales, for LVO among ACI (accuracies LAMS, 0.70; other scales, 0.62-0.68) and CSC-appropriate (accuracies LAMS, 0.73; other scales, 0.56-0.73). CONCLUSIONS: The LAMS performed in the field by paramedics identifies LVO and CSC-appropriate patients with good accuracy. The LAMS performs comparably or better than more extended prehospital scales and the full National Institutes of Health Stroke Scale.

Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-ß Antibodies and ω-3 Not Working in Clinical Trials?

This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-ß1 - 42 (Aß) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aß. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

Peptide Composition of Stroke Causing Emboli Correlate with Serum Markers of Atherosclerosis and Inflammation.

INTRODUCTION: The specific protein composition of stroke-causing emboli is unknown. Because ischemic stroke has a varied etiology, it is possible that the composition of the thrombus from which an embolus originated will have distinctive molecular characteristics reflective of the underlying pathophysiology. We used mass spectrometry to evaluate the protein composition of retrieved emboli from patients with differing stroke etiologies and correlated the protein levels to serum predictors of atherosclerosis. METHODS: Emboli from 20 consecutive acute stroke patients were retrieved by thrombectomy during routine stroke care. Thrombus proteins were extracted, digested, and multidimensional fractionation of peptides was performed. Fractionated peptides underwent nano-liquid chromatography with tandem mass spectrometry. Spectra were searched using Mascot software in which results with p < 0.05 (95% confidence interval) were considered significant and indicating identity. The results were correlated to A1C, low-density lipoprotein (LDL), and erythrocyte sedimentation rate (ESR) taken on admission. RESULTS: Eleven patients had atrial fibrillation, four had significant proximal vessel atherosclerosis, two were cryptogenic, and three had other identified stroke risk factors (left ventricular thrombus, dissection, endocarditis). Eighty-one common proteins (e.g., hemoglobin, fibrin, actin) were found in all 20 emboli. Serum LDL levels correlated with Septin-2 (rs = 0.78, p = 0.028), Phosphoglycerate Kinase 1 (rs = 0.75, p = 0.036), Integrin Alpha-M (rs = 0.68, p = 0.033) and Glucose-6-phosphate dehydrogenase (rs = 0.63, p = 0.05). Septin-7 levels inversely correlated to ESR (rs = -0.84, p = 0.01). No significant protein correlations to A1C or tPA use were found. CONCLUSION: Our exploratory study presents mass spectrometry analysis of thrombi retrieved from acute stroke patients and correlates the thrombus proteome to clinical features of the patient. Notably, we found proteins associated with inflammation (e.g., Integrin Alpha-M) in emboli from patients with high LDL. Although these findings are tempered by a small sample size, we provide preliminary support for the feasibility of utilizing proteomic analysis of emboli to discover proteins that may be used as markers for stroke etiology.

Paramedic Initiation of Neuroprotective Agent Infusions: Successful Achievement of Target Blood Levels and Attained Level Effect on Clinical Outcomes in the FAST-MAG Pivotal Trial (Field Administration of Stroke Therapy - Magnesium).

BACKGROUND AND PURPOSE: Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome. METHODS: The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy - Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation. RESULTS: Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD±14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (±0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death. CONCLUSIONS: Paramedic infusion initiation using gravity-controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke.

A Dedicated Spanish Language Line Increases Enrollment of Hispanics Into Prehospital Clinical Research.

BACKGROUND AND PURPOSE: Novel methods are needed to reduce the disparity of Hispanic enrollment in stroke clinical trials. Prehospital enrollment using a dedicated Spanish language line may help overcome this bias. METHODS: Subjects or legally authorized representatives provided information on race and ethnicity for all cases enrolled in the FAST-MAG clinical trial (Field Administration of Stroke Therapy-Magnesium), a prehospital phase 3 randomized study of intravenous magnesium for neuroprotection. One of 2 in-ambulance cell phones (in English or Spanish) was used to obtain informed content in the field. We describe the yield and characteristics of subjects enrolled via Spanish line. RESULTS: There were 1700 subjects enrolled from 2005 to 2012, of which 402 (24%) identified as Hispanic ethnicity. Study racial makeup was 1325 (78%) white, 219 (13%) black, and 139 (8%) Asian. The dedicated Spanish line was used for 195 (12%) enrollments. Spanish-line enrollments were younger (65 versus 70 years old; P<0.001), more likely to identify as Hispanic (98% versus 14%; P<0.001), and more likely to present with intracerebral hemorrhage (36% versus 21%; P<0.001). CONCLUSIONS: The use of a dedicated Spanish language enrollment line allowed for greater enrollment of Hispanics, a population with significantly different baseline characteristics. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059332.

Field Validation of the Los Angeles Motor Scale as a Tool for Paramedic Assessment of Stroke Severity.

BACKGROUND AND PURPOSE: The Los Angeles Motor Scale (LAMS) is a 3-item, 0- to 10-point motor stroke-deficit scale developed for prehospital use. We assessed the convergent, divergent, and predictive validity of the LAMS when performed by paramedics in the field at multiple sites in a large and diverse geographic region. METHODS: We analyzed early assessment and outcome data prospectively gathered in the FAST-MAG trial (Field Administration of Stroke Therapy-Magnesium phase 3) among patients with acute cerebrovascular disease (cerebral ischemia and intracranial hemorrhage) within 2 hours of onset, transported by 315 ambulances to 60 receiving hospitals. RESULTS: Among 1632 acute cerebrovascular disease patients (age 70±13 years, male 57.5%), time from onset to prehospital LAMS was median 30 minutes (interquartile range 20-50), onset to early postarrival (EPA) LAMS was 145 minutes (interquartile range 119-180), and onset to EPA National Institutes of Health Stroke Scale was 150 minutes (interquartile range 120-180). Between the prehospital and EPA assessments, LAMS scores were stable in 40.5%, improved in 37.6%, and worsened in 21.9%. In tests of convergent validity, against the EPA National Institutes of Health Stroke Scale, correlations were r=0.49 for the prehospital LAMS and r=0.89 for the EPA LAMS. Prehospital LAMS scores did diverge from the prehospital Glasgow Coma Scale, r=-0.22. Predictive accuracy (adjusted C statistics) for nondisabled 3-month outcome was as follows: prehospital LAMS, 0.76 (95% confidence interval 0.74-0.78); EPA LAMS, 0.85 (95% confidence interval 0.83-0.87); and EPA National Institutes of Health Stroke Scale, 0.87 (95% confidence interval 0.85-0.88). CONCLUSIONS: In this multicenter, prospective, prehospital study, the LAMS showed good to excellent convergent, divergent, and predictive validity, further establishing it as a validated instrument to characterize stroke severity in the field.

Critical review of the Appropriate Use Criteria for amyloid imaging: Effect on diagnosis and patient care.

INTRODUCTION: The utility of the Appropriate Use Criteria (AUC) for amyloid imaging is not established. METHODS: Fifty-three cognitively impaired patients with clinical F18-florbetapir imaging were classified as early and late onset, as well as AUC-consistent or AUC-inconsistent. Chi-square statistics and t test were used to compare demographic characteristics and clinical outcomes as appropriate. RESULTS: Early-onset patients were more likely to be amyloid positive. Change in diagnosis was more frequent in late-onset cases. Change in therapy was more common in early-onset cases. AUC-consistent and AUC-inconsistent cases had comparable rates of amyloid positivity. We saw no difference in the rate of treatment changes in the AUC-consistent group as opposed to the AUC-inconsistent group. DISCUSSION: The primary role of amyloid imaging in the early-onset group was to confirm the clinically suspected etiology, and in the late-onset group in detecting amyloid-negative cases. The rate of therapeutic changes was significantly greater in the early-onset cases.